3,3-Dialkylated 4-chromanones, and particularly 6-fluoro-3,3-dimethyl-4-chromanone and 3,3-dimethyl-4-chromanone, are key intermediates in the preparation of agents that are useful for the treatment of depression [See U.S. Pat. No. 6,110,956, incorporated herein by reference].
The synthesis of 3,3-dialkylated 4-chromanones by direct alkylation is rendered difficult by the tendency to undergo ring opening to a phenolate anion under basic conditions [See Brown, P. E. and Islam, Q., J. Chem. Research (M) (1988) 1634; Anastasis, P. et al., J. Chem. Research (M) (1989) 429]. Even with these established methods of alkylation, mono alkylation usually dominates, and a second alkylation often either results in low yields or in ring opening [See Anastasis, P. and Brown, P. E., J. Chem. Soc. Perkin Trans. I (1983) 197]. Given the importance of 3,3-dialkylated 4-chromanones, and particularly 6-fluoro-3,3-dimethyl-4-chromanone and 3,3-dimethyl-4-chromanone, it can be seen that improved synthetic routes for their preparation are needed. This invention is directed to these, as well as other, important ends.